Ketan Dhatariya

Higher muscle protein synthesis in women than men across the lifespan, and failure of androgen administration to amend age-related decrements

We investigated age and sex effects and determined whether androgen replacement in elderly individuals (≥60 yr) could augment protein synthesis. Thirty young men and 32 young women (18‐31 yr) were studied once, whereas 87 elderly men were studied before and after 1 yr of treatment with 5 mg/day testosterone (T), 75 mg/day dehydroepiandrosterone (DHEA), or placebo (P);and 57 elderly women were studied before and after 1 yr of treatment with 50 mg/day DHEA or P. [15N]Phenylalanine and [2H4]tyrosine tracers were infused, with measurements in plasma and vastus lateralis muscle. Whole‐body protein synthesis per fat‐free mass and muscle protein fractional synthesis rate (FSR) were lower in elderly than in young individuals (P< 0.001), not significantly affected by hormone treatments, and higher in women than in men (P<0.0001), with no sex × age interaction. In regression analyses, peak O2 consumption (VO2peak), resting energy expenditure (REE), and sex were independently associated with muscle FSR, as were VO2peak, REE, and interactions of sex with insulin‐like growth factor‐II and insulin for whole‐body protein synthesis. Women maintain higher protein synthesis than men across the lifespan as rates decline in both sexes, and neither full replacement of DHEA (in elderly men and women) nor partial replacement of bioavailable T (in elderly men) is able to amend the age‐related declines.— Henderson, G. C., Dhatariya, K., Ford, G. C., Klaus, K. A., Basu, R., Rizza, R. A., Jensen, M. D., Khosla, S., OBrien, P., Nair, K. S. Higher muscle protein synthesis in women than men across the lifespan, and failure of androgen administration to amend age‐related decrements. FASEB J. 23, 631–641 (2009)

Effect of Insulin Deprivation on Muscle Mitochondrial ATP Production and Gene Transcript Levels in Type 1 Diabetic Subjects

OBJECTIVE—Muscle mitochondrial dysfunction occurs in many insulin-resistant states, such as type 2 diabetes, prompting a hypothesis that mitochondrial dysfunction may cause insulin resistance. We determined the impact of insulin deficiency on muscle mitochondrial ATP production by temporarily depriving type 1 diabetic patients of insulin treatment. RESEARCH DESIGN AND METHODS—We withdrew insulin for 8.6 ± 0.6 h in nine C-peptide–negative type 1 diabetic subjects and measured muscle mitochondrial ATP production and gene transcript levels (gene array and real-time quantitative PCR) and compared with insulin-treated state. We also measured oxygen consumption (indirect calorimetry); plasma levels of glucagon, bicarbonate, and other substrates; and urinary nitrogen. RESULTS—Withdrawal of insulin resulted in increased plasma glucose, branched chain amino acids, nonesterified fatty acids, β-hydroxybutyrate, and urinary nitrogen but no change in bicarbonate. Insulin deprivation decreased muscle mitochondrial ATP production rate (MAPR) despite an increase in whole-body oxygen consumption and altered expression of many muscle mitochondrial gene transcripts. Transcript levels of genes involved in oxidative phosphorylation were decreased, whereas those involved in vascular endothelial growth factor (VEGF) signaling, inflammation, cytoskeleton signaling, and integrin signaling pathways were increased. CONCLUSIONS—Insulin deficiency and associated metabolic changes reduce muscle MAPR and expression of oxidative phosphorylation genes in type 1 diabetes despite an increase in whole-body oxygen consumption. Increase in transcript levels of genes involved in VEGF, inflammation, cytoskeleton, and integrin signaling pathways suggest that vascular factors and cell proliferation that may interact with mitochondrial changes occurred.

Dehydroepiandrosterone: Is There a Role for Replacement?

Dehydroepiandrosterone (DHEA) and its sulfated ester are found in high concentrations in the plasma; however, their role in normal human physiology, other than as precursors for sex hormones, remains incompletely defined. Studies of rodent models have shown that these hormones have beneficial effects on a wide variety of conditions, such as diabetes, obesity, immune function, atherosclerosis, and many of the disorders associated with normal aging. However, rodents are not the best models to study the actions of these hormones because they have very little endogenous DHEA; thus, the doses given to these animals are usually suprapharmacological. Human studies have been performed to determine the potential beneficial effects of DHEA replacement in persons with low DHEA levels. Results have been conflicting. Human studies suggest a potential role for DHEA replacement in persons who have undergone adrenalectomy and possibly in the aging population. However, long-term studies assessing the benefits vs adverse effects must be done before DHEA replacement can be recommended.

Effect of Dehydroepiandrosterone Replacement on Lipoprotein Profile in Hypoadrenal Women

CONTEXTnLevels of dehydroepiandrosterone (DHEA) and its sulfate form (DHEAS) are inversely associated with cardiovascular mortality in men but not women. Very little evidence is available on the impact of DHEA administration on lipoprotein profile in women. DHEAS levels are very low/undetectable in hypoadrenal women.nnnOBJECTIVEnThe objective of the study was to determine the impact of DHEA replacement on lipoprotein profile in hypoadrenal women.nnnDESIGN AND SETTINGnA double-blind, randomized, placebo-controlled, cross-over design study was conducted at the Mayo Clinic.nnnPARTICIPANTSnThirty-three hypoadrenal Caucasian women (mean +/- sd; age 50.3 +/- 15.2 yr, body mass index 26.6 +/- 4.4 kg/m(2)) took part in the study.nnnINTERVENTIONnStudy participants were assigned to receive either a placebo or 50 mg/d of DHEA for 3 months each. Lipid levels and lipoprotein profile were analyzed using the Lipo Science Lipoprotein nuclear magnetic resonance system.nnnMAIN OUTCOME MEASURESnChanges in various lipoprotein sizes and levels were measured.nnnRESULTSnThe DHEA period had higher plasma DHEAS levels than during placebo (<0.3 +/- 0.0 vs. 3.5 +/- 1.3 nmol/liter, P < 0.001). DHEA replacement significantly reduced total cholesterol (20.0 vs. -22, P = 0.02) and high-density lipoprotein (HDL) levels (2.0 vs. -6.0, P = 0.006) and tends to reduce triglyceride and total low-density lipoprotein levels. Although, DHEA replacement had no effect on low-density lipoprotein particle size, it significantly reduced larger HDL particles and to modest extent small HDL particles.nnnCONCLUSIONSnOur study findings showed that oral DHEA administration in hypoadrenal women results in an unfavorable lipoprotein profile. The results warrant long-term studies to determine the impact of DHEA replacement on cardiovascular risk.

Dehydroepiandrosterone Replacement Therapy in Hypoadrenal Women: Protein Anabolism and Skeletal Muscle Function

OBJECTIVEnTo determine whether dehydroepiandrosterone (DHEA) replacement therapy in hypoadrenal women improves performance, muscle protein accretion, and mitochondrial functions.nnnPARTICIPANTS AND METHODSnThirty-three hypoadrenal women were enrolled in the study from May 1, 2002, through May 31, 2003. Twenty-eight completed a 12-week, prospective, randomized, placebo-controlled, crossover study with either daily placebo or 50 mg of DHEA with a 2-week washout period and then crossed over to the other treatment. Body composition, physical performance, whole-body and muscle protein metabolism, and mitochondrial functions were determined.nnnRESULTSnAdministration of DHEA significantly increased plasma levels of DHEA sulfate, testosterone, and androstenedione but did not change body composition, muscle strength, peak aerobic capacity, and whole-body protein turnover or synthesis rates of mitochondrial, sarcoplasmic, or mixed muscle proteins. Muscle mitochondrial oxidative enzymes and messenger RNA (mRNA) levels of genes encoding mitochondrial proteins and nuclear transcription factors did not change after DHEA administration. However, mRNA levels of muscle myosin heavy chain 1 (P=.004), which determines muscle fiber type, and those of insulinlike growth factor binding proteins 4 and 5 significantly decreased (P=.02 and P=.03, respectively).nnnCONCLUSIONnThree months of DHEA administration increased DHEA sulfate and androgen levels but had no effect on physical performance, body composition, protein metabolism, or muscle mitochondrial biogenesis in hypoadrenal women. However, lowering of mRNA levels of binding proteins of insulinlike growth factor 1 and myosin heavy chain 1 suggests potential effects of longterm treatment with DHEA on muscle fiber type.

Research into research

Which research event has had most effect on your work? The “awakenings” of my postencephalitic patients, in 1969. What would be your advice to a newly qualified doctor? Listen— listen minutely, to every patient; refrain from hasty judgments; see every patient as unique; see their condition from their perspective. What complementary/alternative therapies have you tried? Did they work? Music therapy—which has amazing power in many neurological conditions, allowing otherwise disabled parkinsonian patients to walk and talk and demented patients to achieve a brief orientation and clarity. What is your greatest regret? That I did not acquire more mathematical facility. Do you apply subjective moral judgments in your work? I hope I work with moral delicacy, but try to avoid moral judgments. Describe your ethical outlook. I think we are a wayward and dangerous (as well as sublime) species, and that the only hope for (physical and psychic) survival comes partly from civilisation and culture and partly from selfexamination and awareness. I am doubtful of the power of politics, law, government, or religion to improve human behaviour or nature. Have you ever broken one of the ten commandments? Oh dear— lots of them. Where were you in your sibling order, and what did you gain or lose as a result? The youngest of four brothers—so much the youngest, in effect, that I often felt like an only child. This may have given me, for better or worse, a sense both of solitariness and autonomy. Most of us in hospital jobs want to be a consultant. Many people would be satisfied with a District-General-hospital post, with a nice mixture of general medicine, the comfortable on-call rota, specialty outpatient clinics, and possibly the icing on the cake, a little private hospital in the area to finance all those nice little extras one needs from time to time (eg, the holiday, the car, the kids school fees). What about those who want to pursue a life of serious academia? It would seem sensible that to live a life of research, one must have some sort of track record in order to be appointed to a post in which research will play a large part. Thanks to Kenneth Calman (former Chief Medical Officer for England and Wales), all of us have to rotate through centres of excellence for at least part of our time on the scheme and so be exposed to research in those departments. But, unlike the preCalman days, trainees are forced to move on after a year, and so may not have the time (or inclination) to set up and run a project. I lived out in District-General-hospital land for many years before being exposed to this world and although not discouraged whilst I was there, I was certainly not actively encouraged to do any form of research. I was fulfilling my service commitment, learning on the job, and that was it. When suddenly exposed to this plethora of papers, meetings, lectures, and professors I suddenly realised that this was the kind of life I’d like to live—not being tied to the local BUPA. Suddenly I was too young, too thick—and certainly too inexperienced—to be a consultant. Research beckoned. I felt that I had it in me to do some research. To be able to focus on the minutiae of a specific subject that interested me for 2 or 3 years was in my grasp. This, of course is not enough. How do you pick your research topic? Where should it be done? The need to write a good proposal and do all the research involved is almost overwhelming. Who can tell you where to apply or how to write that proposal and what to put down? Funding seems to be such a hit and miss thing. There are different levels of funding and there is definitely a hierarchy of prestige— there are those grants that are given to the individual for a specific proposal and those funds which are given to the head of a unit to appoint any person that they see fit to do the job. The latter definitely seems to be looked down upon by the holders of the former. At the end of the day does it make a difference to how one is perceived? The letters at the end of the name are the same regardless of how they are come by. Maybe the research is for the CV and the desire to get a good job and not for altruistic benefit of mankind, nor the commitment for self betterment. There is, of course that difficult question—does having research experience make us better doctors? There may be a sacrifice being made for that more structured training that Calman has imposed—a consultant who may not have any research behind them, or worse, one who may not be able to critically appraise data because they lack the skills to do so. If this becomes the case then when the current trainees themselves sit on the consultant appointment committees, there may be gaps in the system. For this reason alone, maybe research grants should be made more readily available. Get rid of the stigma and all grants should be prestigious and well thought of.